263 research outputs found
Biocatalytic synthesis of two pharmacologically active compounds: (S)-pramipexole and its enantiomer, dexpramipexole.
No full textBiocatalytic synthesis of two pharmacologically active compounds:
(S)-pramipexole and its enantiomer, dexpramipexole
Samuele Ciceri,a,* Patrizia Ferraboschi,a Paride Grisenti,b Matteo Moric and Fiorella Meneghettic
a Department of Medical Biotechnology and Translational Medicine, University of Milan, Via C. Saldini 50, 20133 Milano, Italy
b Chemical-Pharmaceutical Consulting and IP Management, Viale G. da Cermenate 58, 20141 Milano, Italy
c Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy
*[email protected]
Many pharmaceutically active compounds contain a chiral core inside their structure. Therefore, compounds formed highly selectively are valuable products. The chemo-, regio-, and stereo-selectivity required could be achieved using biocatalysts (enzymes or microorganisms), which can work on a wide range of substrates, in mild reaction conditions and not only in aqueous solutions, but also in organic solvents. Moreover, biocatalysis meets the green chemistry principles.
Our research work focuses on the biocatalytic synthesis of key building blocks affording to pharmaceutically active compounds, currently used in therapy [1, 2].
Following this approach, we were able to synthetize the enantiopure key intermediates of (S)-pramipexole, a synthetic dopaminergic agonist utilized as anti-Parkinson drug, and (R)-pramipexole, which has been studied as therapeutic agent against Amyotrophic Lateral Sclerosis (ALS) and now it has found new interest for the potential treatment of Eosinophilic Asthma and Hypereosinophilic Syndrome.
Two different biocatalytic approach allowed us to stereoselectively synthesize these compounds:
1) After the investigation of the activity and selectivity of different microorganisms (especially yeasts), we obtained the enantiomerically pure synthons for the preparation of (S)- and (R)-pramipexole by means of Saccharomyces cerevisiae, the common baker’s yeast, a cheap and easy to handle microorganism.
2) The two enantiomerically pure synthons were achieved by means of a double kinetic resolution catalized by a commercially available purified enzyme, Lipase A from Candida antarctica, under irreversible transesterification conditions.
The definition of the stereochemistry of the two enantiomers was also carried out by means of single crystal X-ray analysis.
References
[1] Ciceri, S.; Ciuffreda, P.; Grisenti, P. and Ferraboschi, P. Synthesis of the antitumoral nucleoside capecitabine through a chemo-enzymatic approach Tetrahedron Lett. 2015, 56, 5909-5913.
[2] Ciceri, S.; Grisenti, P.; Reza Elahi, S. and Ferraboschi, P. A New Chemoenzymatic Synthesis of the Chiral Key Intermediate of the Antiepileptic Brivaracetam Molecules 2018, 23, 2206
A NEW FLEXIBLE SYNTHESIS OF (R,S)-MEVALONOLACTONE
No full textBy selective ozonolysis of the diene (5), a new synthesis of (R,S)-mevalonolactone (1a) has been developed, which can be adapted to other compounds related to (1a). This has been exemplified by the synthesis of the monodeuteriated triol (4d) and dideuteriated mevalonolactone (1d)
A CHEMOENZYMATIC APPROACH TO ENANTIOMERICALLY PURE (R)-2,3-EPOXY-2-(4-PENTENYL)-PROPANOL, AND (S)-2,3-EPOXY-2-(4-PENTENYL)-PROPANOL, A CHIRAL BUILDING BLOCK FOR THE SYNTHESIS OF (R)-FRONTALIN AND (S)-FRONTALIN
No full textEnantiomerically pure (R)- and (S)-epoxyalcohols 1, chiral intermediates for the synthesis of (R)- and (S)-frontalin 2, are prepared by Pseudomonas fluorescens lipase-catalyzed transesterification in dichloromethane
Biohydrogenation of unsaturated compounds by Saccharomyces cerevisiae. 1. Stereochemical aspects of the reaction and preparation of useful bifunctional chiral synthons
No full textEthyl 4,4-dimethoxy-3-methylbut-2-enoate (1; R = CO2Et) has been prepared as a mixture of (E)-and (Z)-isomers, the (E)/(Z) ratio depending on the base used. Each isomeric mixture of (1a) and (1b) has been used as substrate for biohydrogenation with fermenting Saccharomyces cerevisiae (baker's yeast) and the (Z)-isomer seems to be the preferred substrate. (E)-Unsaturated alcohols such as (3a) and (5d) are not reduced to the corresponding saturated hydroxy derivatives by baker's yeast. The (E)-aldehyde (3c) and its acetal (3d) are mainly reduced to the corresponding (E)-alcohol (3a), the saturated hydroxy ester (2a) being formed to a minor extent, especially with (3d). In contrast, biohydrogenation is also successful with the (E)-isomers of compounds (3e), (3f), and (3b) (R2 = alkyl or alkenyl). If the allylic oxygenated group to be reduced is not α-methyl substituted, reduction to the corresponding saturated alcohols readily occurs with the (E)-isomers as in the case of (5f). For this last biohydrogenation, the stereochemistry of the methyl-bearing carbon has been established by chemical correlations. The α,β-disubstituted allylic acetal (6a) is not biohydrogenated by the yeast, but a mixture of unsaturated hydroxy ester (6b) and γ-hydroxy lacton
A chemoenzymatic synthesis of enantiomerically pure (R)- and (S)-2-methyldecan-1-ol
No full text(R)- and (S)-2-methyldecan-1-ol 3a has been prepared in > 98% enantiomeric excess (ee) by transesterification with vinyl acetate in chloroform in the presence of Pseudomonas fluorescens lipase. Oxidation of the alcohol 3a affords nearly optically pure 2-methyldecanoic acid 3b
A biocatalytic approach to the enantioselective synthesis of (R)- and (S)-malic acid
No full textS)-Diethyl malate 1a was prepared (70-80% yield; > 98% optical purity) by an enantioselective reduction of sodium diethyl oxalacetate 2 by fermenting baker's yeast (Saccharomyces cerevisiae). Other microorganisms were tested for their capability of reducing 2. Most of them afforded (S)-1a-with ee from 8 to 94% and only Candida utilis, Aspergillus niger and Lactobacillus fermentum ILC G18D preferentially reduced compound 2 to (R)-1a. (R)-Dimethyl malate 1b was obtained from (R,S)-malate 1b by hydrolysis with pig liver esterase (PLE), the highest ee (93%) being realized at 0-degrees-C in 20% aqueous methanol. Enzymatic hydrolyses of protected malates 1d and 1e did not lead to improvement of the ee
An efficient chemo-enzymatic approach to the enantioselective synthesis of 2-methyl-1,3-propamedical derivatives
No full textLipase-catalyzed transesterification of 2-methyl-1,3-propanediol 1 in chloroform affords enantiomerically pure (S)-(-)-acetate 2, from which the (R)-(+)-silyl ethers 4a-b can be efficiently prepared (>98% ee). The (S)-TBDPS derivative 4b could be also efficiently and enantioselectively prepared by the same enzymatic procedure, starting from racemic 5b
Enzymatic synthesis of enantiomerically pure chiral synthons: Lipase-catalyzed resolution of (R / S, 4 E)-2-Methyl-4-hexen-l-ol
No full textThe synthetically useful chiral synthons R and S (4E)-2-methyl-4-hexen-1-ol (1a) can be prepared enantiomerically pure by an enantioselective transacetylation with vinyl acetate of racemic 1a in dichloromethane catalyzed by a lipase from Pseudomonas fluorescens (PFL)
Baker's yeast-mediated reduction of α-hydroxy ketones and derivatives: The steric course of the biotransformation
No full textThe results from the baker's yeast-mediated reduction of the acetates 3a-d and the methyl ethers 5a-d were compared with the same biotransformation which converts the alpha-hydroxy ketones 1a-d into the (R)-diols 2a-d (90-98%ee); the acetates 3a-d afford the (S)-monoacetates 4a-d (72-94% ee) and the methyl ethers 5a-d are reduced to the (R)-monoethers 6a-d (64-76% ee)
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